Metastasis, or metastatic disease, is the spread of a cancer from an originating tissue or organ to another tissue or organ. The cells which constitute the primary cancerous tumour commonly undergo metaplasia, followed by dysplasia and then anaplasia, resulting in a malignant phenotype. This malignant phenotype allows for intravasation into the circulation, followed by extravasation to a second site for tumourigenesis. After the tumour cells have migrated to another site, they re-penetrate the vessel or walls and continue to multiply, eventually forming another clinically detectable tumour (secondary tumours). Whilst treatment regimens and therapies for primary tumours are much better understood, with improved efficacy and success rates, and whilst some types of metastatic cancer can be cured with such current treatments, most metastatic cancers show poor response. Treatments for metastatic disease do exist, such as systemic therapy (chemotherapy, biological therapy, targeted therapy, hormonal therapy), local therapy (surgery, radiation therapy), or a combination of these treatments. However, most often the primary goal of these treatments is to control the growth of the cancer or to relieve symptoms caused by same. It is therefore generally considered that most people who die of cancer die of metastatic disease.
Therefore, improved understanding of cancer progression towards aggressive metastatic forms and tumour cell-specific molecular pathways is necessary to improve and lead to new therapies.
NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a protein complex that controls the transcription of DNA, and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, ultraviolet irradiation, oxidized LDL, and bacterial or viral antigens. Members of the NF-κB family can both induce and repress gene expression through binding to DNA sequences, and regulate numerous genes that control programmed cell death, cell adhesion, proliferation, immunity and inflammation.
It is known that NF-κB provides a link between inflammation and cancer progression. Further, NF-κB is widely used by eukaryotic cells as a regulator of genes that control cell proliferation and cell survival. As such, many different types of human tumours have deregulated NF-κB: that is, NF-κB is constitutively active. Deregulated NF-κB has been documented in many cancers, including solid cancers such as breast, melanoma, lung, colon, pancreatic, oesophageal, and also haematological malignancies. For example, it has been shown that increased NF-κB activation was evident in 86% of HER2+/ER− breast cancers and in 33% of basal like cancers, which are associated with a shortened disease-free interval, poor survival and resistance to cancer therapy. Moreover, NF-κB activation in tumour cells, tumour-associated stromal and endothelial cells is thought to play a role in tumour progression and invasion.
B-cell Lymphoma 3 (Bcl-3) is a proto-oncogene modulating NF-κB signaling, which was first identified as a chromosome translocation in B-cell chronic lymphocytic leukaemia. Deregulated Bcl-3 over-expression has been reported in numerous tumours including several leukaemias and lymphomas, such as anaplastic large cell lymphomas (ALCLs), classic Hodgkin lymphomas (cHL) and non-Hodgkin's lymphoma. Additionally, deregulated expression has also been observed in solid tumour cancers, such as breast cancer, nasopharyngeal carcinoma, and hepatocarcinomas.
A role for NF-κB and Bcl-3 in metastatic colorectal cancer has also been shown, where it was observed that NF-κB activation occurs prior to metastatic spread. Notably, Bcl-3 expression was also observed in normal and tumour tissue, but a correlation between nuclear Bcl-3 and patient survival was observed. Bcl-3 expression has also been found to be increased in breast cancer cell lines and patient breast cancer samples versus non-tumorigenic cell lines and normal adjacent tissue, respectively. Cells overexpressing Bcl-3 also resulted in a significantly higher number of tumours which supports the role for Bcl-3 in breast cancer progression.
The underlying oncogenic function of Bcl-3 has never been fully elucidated. However, established thinking based on experiments performed on cancer cell lines in vitro is that it has a role in increased cellular proliferation and cell survival. It was previously shown that Bcl-3 specifically promotes the formation of metastasis of ErbB2 breast cancer driven tumours. Although primary tumour growth in the Bcl-3 deficient ErbB2 (MMTV/neu) murine model was not affected, it was shown that the occurrence of developed lung metastasis from a primary breast tumour was significantly reduced by 40%. Moreover, a significant reduction in mitotic index and apoptosis was observed in secondary tumour lesions but not in primary tumours. Furthermore, through gene expression knock down studies, it was shown that deletion of Bcl-3 resulted in an 80% decrease in lung metastases, which was attributed to loss of cell migration but importantly with no effect upon normal mammary function or overall systemic viability. The implication from these observations is that specific targeting of individual NF-κB subunits or their co-activators may be a more beneficial therapeutic strategy than suppressing their upstream regulators which appear to exhibit detrimental systemic toxicity. This therefore suggests Bcl-3 may represent a suitable therapeutic target for preventing cancer metastasis and secondary tumour formation.
Thus, there is a need to develop modulators of Bcl-3 for treating or preventing diseases or disorders in which Bcl-3 and/or NF-κB play a role.